ONCASPAR 750U / ml injection / infusion solution medication leaflet

Oncaspar 750 U/ml powder for solution for injection/infusion.

Each vial contains 3,750 Units (U)** of pegaspargase*.

After reconstitution, 1 ml of solution contains 750 U pegaspargase (750 U/ml).

* The active substance is a covalent conjugate of Escherichia coli-derived L-asparaginase withmonomethoxypolyethylene glycol

**One unit is defined as the quantity of enzyme required to liberate 1 µmol ammonia per minute atpH 7.3 and 37°C

The potency of this medicinal product should not be compared to the one of another pegylated ornon-pegylated protein of the same therapeutic class. For more information, see section 5.1.

For the full list of excipients, see section 6.1.

Powder for solution for injection/infusion.

White to off-white powder.

Oncaspar is indicated as a component of antineoplastic combination therapy in acute lymphoblasticleukaemia (ALL) in paediatric patients from birth to 18 years, and adult patients.

Oncaspar should be prescribed and administered by physicians and/or health care personnelexperienced in the use of antineoplastic products. It should only be given in a hospital setting whereappropriate resuscitation equipment is available. Patients should be closely monitored for any adversereactions throughout the administration period (see section 4.4).

Oncaspar is usually administered as part of combination chemotherapy protocols with otherantineoplastic agents (see also section 4.5).

Recommended premedication

Premedicate patients with paracetamol, an H-1 receptor blocker (e.g. diphenhydramine), and an H-2receptor blocker (e.g. famotidine) 30-60 minutes prior to administration of Oncaspar to decrease therisk and severity of both infusion and hypersensitivity reactions (see section 4.4).

Paediatric patients and adults ≤21 years

The recommended dose in patients with a body surface area (BSA) ≥0.6 m2 and who are ≤21 years ofage is 2,500 U of pegaspargase (equivalent to 3.3 ml Oncaspar)/m2 body surface area every 14 days.

Children with a body surface area <0.6 m2 should receive 82.5 U of pegaspargase (equivalent to 0.1 ml

Oncaspar)/kg body weight every 14 days.

Adults >21 years

Unless otherwise prescribed, the recommended posology in adults aged >21 years is 2,000 U ofpegaspargase (equivalent to 2.67 ml Oncaspar)/m2 body surface area every 14 days.

Treatment may be monitored based on the trough serum asparaginase activity measured before thenext administration of pegaspargase. If asparaginase activity values fail to reach target levels, a switchto a different asparaginase preparation could be considered (see section 4.4).

As pegaspargase is a protein with a high molecular weight, it is not excreted renally, and no doseadjustment is necessary in patients with renal impairment.

No dose adjustment is necessary in patients with hepatic impairment.

There are limited data available for patients older than 65 years.

Oncaspar can be given by intramuscular (IM) injection or intravenous (IV) infusion.

For smaller volumes, the preferred route of administration is intramuscular. When Oncaspar is givenby intramuscular injection the volume injected at one site should not exceed 2 ml in children andadolescents and 3 ml in adults. If a higher volume is given, the dose should be divided and given atseveral injection sites.

Intravenous infusion of Oncaspar is usually given over a period of 1 to 2 hours in 100 ml sodiumchloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution.

The diluted solution can be given together with an already-running infusion of either sodium chloride9 mg/ml or 5% glucose. Do not infuse other medicinal products through the same intravenous lineduring administration of Oncaspar.

For instructions on reconstitution and dilution of this medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment (bilirubin >3 times upper limit of normal [ULN]; transaminases >10 times

ULN).

History of serious thrombosis with prior L-asparaginase therapy.

History of pancreatitis, including pancreatitis related to previous L-asparaginase therapy (seesection 4.4).

History of serious haemorrhagic events with prior L-asparaginase therapy (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Asparaginase antibodies

The presence of anti-asparaginase antibodies may be associated with low asparaginase activity levelsdue to potential neutralising activity of these antibodies. In such cases, a switch to a differentasparaginase preparation should be considered.

Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to ruleout an accelerated reduction of asparaginase activity.

Hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, can occur duringtherapy, including in patients with known hypersensitivity to E. coli derived asparaginaseformulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling,erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash (see sections 4.3and 4.8).

Premedicate patients 30-60 minutes prior to administration of Oncaspar (see section 4.2).

As a routine precautionary measure, the patient should be monitored for an hour after administration;resuscitation equipment and other appropriate means for the treatment of anaphylaxis should beavailable (epinephrine, oxygen, intravenous steroids, etc.). Oncaspar should be discontinued inpatients with serious hypersensitivity reactions (see sections 4.3 and 4.8). Depending on the severity ofthe symptoms, administration of antihistamines, corticosteroids and vasopressors may be indicated asa counter-measure.

Pancreatic effects

Pancreatitis, including haemorrhagic or necrotising pancreatitis with fatal outcomes, has been reportedin patients receiving Oncaspar (see section 4.8).

Patients should be informed of the signs and symptoms of pancreatitis which, if left untreated, couldbecome fatal.

If pancreatitis is suspected, Oncaspar should be discontinued; if pancreatitis is confirmed, Oncasparshould not be restarted.

Serum amylase and/or lipase levels should be monitored frequently to identify early signs ofpancreatic inflammation. Blood glucose levels should be monitored, as impaired glucose tolerancemay occur with concomitant use of Oncaspar with prednisone.

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receivingpegaspargase (see section 4.8). Oncaspar should be discontinued in patients with serious thromboticevents.

Increased prothrombin time (PT), increased partial thromboplastin time (PTT), hypofibrinogenaemiaand antithrombin III decrease can occur in patients receiving pegaspargase. Coagulation parametersshould be monitored at baseline and periodically during and after treatment, particularly when othermedicinal products with anticoagulant effects (such as acetylsalicylic acid and non-steroidalanti-inflammatory medicinal products) are used simultaneously (see section 4.5), or when concomitantchemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered. Whenthere is a marked decrease in fibrinogen or antithrombin III (ATIII) deficiency, consider appropriatereplacement therapy.

In the presence of glucocorticoids, osteonecrosis (avascular necrosis) is a possible complication ofhypercoagulability observed in children and adolescents with a higher incidence seen in girls (seesection 4.5 and 4.8). Therefore, a close monitoring in children and adolescents’ patients isrecommended in order to detect any clinical signs/symptoms of osteonecrosis. Clinical judgement ofthe treating physician should guide the management plan of each patient based on individualbenefit/risk assessment as per standard guidelines of treatment of ALL and supportive care principles.

Combination therapy with Oncaspar and other hepatotoxic products can result in severe hepatictoxicity.

Caution is required when Oncaspar is given in combination with hepatotoxic products, especially ifthere is pre-existing hepatic impairment. Patients should be monitored for changes in liver functionparameters.

There may be an increased risk of hepatotoxicity in Philadelphia chromosome positive patients, forwhom treatment with tyrosine kinase inhibitors (e.g., imatinib) is combined with L-asparaginasetherapy. This should be taken into account when considering the use of Oncaspar in these patientpopulations.

Hepatic veno-occlusive disease (VOD), including severe, life-threatening and potentially fatal caseshave been observed in patients treated with Oncaspar in combination with standard chemotherapy,including during the induction phase of multiphase chemotherapy (see section 4.8).

Signs and symptoms of VOD include rapid weight gain, fluid retention with ascites, hepatomegaly,thrombocytopenia and rapid increase of bilirubin. The identification of risk factors like pre-existingliver disease or history of VOD is essential for its prevention. Prompt recognition and appropriatemanagement of VOD remain imperative. Patients who experience this condition should be treatedaccording to standard medical practice.

Due to the risk of hyperbilirubinaemia, it is recommended to monitor bilirubin levels at baseline andprior to each dose.

Central nervous system effects

Combination therapy with Oncaspar can result in central nervous system toxicity. Cases ofencephalopathy (including reversible posterior leukoencephalopathy syndrome) have been reported(see section 4.8).

Oncaspar may cause central nervous system signs and symptoms manifesting as somnolence,confusion, convulsions. Patients should be closely monitored for such symptoms, especially if

Oncaspar is used in association with neurotoxic products (such as vincristine and methotrexate; seesection 4.5),

Pegaspargase may cause myelosuppression, either directly or indirectly (by altering myelosuppressiveeffects of other agents such as methotrexate or 6-mercaptopurine). Therefore, use of Oncaspar couldincrease the risk of infections.

The decrease in the number of circulating lymphoblasts is often quite marked, and normal or too lowleukocyte counts are often seen in the first days after the start of therapy. This can be associated with amarked rise in the serum uric acid level. Uric acid nephropathy may develop. To monitor thetherapeutic effect, the peripheral blood count and the patient’s bone marrow should be monitoredclosely.

Hyperammonaemia

Asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid andglutamic acid, with ammonia as the shared by-product of both reactions (see section 5.1). Intravenousadministration of asparaginase may therefore cause serum levels of ammonia to rise sharply followingadministration.

The symptoms of hyperammonaemia are often transient in nature and can include: nausea, vomiting,headache, dizziness and rash. In severe cases, encephalopathy can develop with or without hepaticimpairment, especially in older adults, which can be life-threatening or fatal. If symptoms ofhyperammonaemia exist, ammonia levels should be monitored closely.

Effective non-oral method of contraception must be used during Oncaspar treatment and for atleast 6 months after Oncaspar discontinuation. Since an indirect interaction between the oralcontraceptives and pegaspargase cannot be ruled out, the use of oral contraception is not considered anacceptable method of contraception (see sections 4.5 and 4.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say, essentially‘sodium-free’.

The decrease in serum proteins caused by pegaspargase can increase the toxicity of other medicinalproducts that are protein bound.

In addition, by inhibiting protein synthesis and cell division, pegaspargase can disturb the mechanismof action of other substances which require cell division for their effect, e.g., methotrexate.

Methotrexate and cytarabine can interact differently with Oncaspar: their prior administration canincrease the action of pegaspargase synergistically. If these substances are given subsequently, theeffect of pegaspargase can be weakened antagonistically.

Pegaspargase can interfere with metabolism and clearance of other medicinal products, based on itseffects on protein synthesis and hepatic function, as well as from its combined use with otherchemotherapy products known to interact with CYP enzymes.

The use of Oncaspar can lead to fluctuation in coagulation factors. This can promote the tendency tobleeding and/or thrombosis. Caution is therefore needed when anticoagulants such as coumarin,heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicinal products aregiven concomitantly, or when concomitant chemotherapy regimen including methotrexate,daunorubicin, corticosteroids is administered.

When glucocorticoids (e.g., prednisone) and pegaspargase are given at the same time, alterations incoagulation parameters (e.g., fall in fibrinogen and antithrombin III deficiency, ATIII) can be morepronounced.

Pegaspargase may increase the risk of glucocorticoid-induced osteonecrosis in children andadolescents when both treatments are given simultaneously, with a higher incidence seen in girls,through a potential increase in exposure of dexamethasone. (see sections 4.4 and 4.8).

Immediately preceding or simultaneous treatment with vincristine can increase the toxicity ofpegaspargase. Administration of Oncaspar before vincristine may increase the neurotoxicity ofvincristine. Therefore, vincristine should be given at least 12 hours prior to administration of Oncasparin order to minimise toxicity.

An indirect interaction cannot be ruled out between pegaspargase and oral contraceptives due topegaspargase hepatotoxicity that may impair the hepatic clearance of oral contraceptives. Therefore,the concomitant use of Oncaspar with oral contraceptives is not recommended. Another method thanoral contraception should be used in women of childbearing potential (see sections 4.4 and 4.6).

Simultaneous vaccination with live vaccines may increase the risk of severe infections attributable tothe immunosuppressive activity of pegaspargase, the presence of the underlying disease andcombination chemotherapy (see section 4.4). Vaccination with live vaccines should therefore be givenno earlier than 3 months after termination of the entire antileukaemic treatment.

Men and women should use effective contraception during treatment and for at least 6 months after

Oncaspar discontinuation. Since an indirect interaction between oral contraceptives and pegaspargasecannot be ruled out , oral contraceptives are not considered sufficiently safe in such clinical situation.

A method other than oral contraception should be used in women of childbearing potential (seesections 4.4 and 4.5).

There are limited data on the use of L-asparaginase and no data on the use of Oncaspar in pregnantwomen. No reproduction studies in animals with pegaspargase were performed but studies in animalswith L-asparaginase have shown teratogenicity (see section 5.3). Therefore and due to itspharmacological properties, Oncaspar should not be used during pregnancy unless the clinicalconditions of the woman require treatment with pegaspargase.

It is not known whether pegaspargase is excreted in breast milk. Based on its pharmacologicalproperties, any risk to the breast-fed newborns/infants cannot be excluded. As a precautionary measure,breast-feeding should be discontinued during treatment with Oncaspar and should not be restarteduntil after discontinuation of Oncaspar.

No studies investigating the effect of pegaspargase on fertility have been performed.

Oncaspar has a major influence on the ability to drive and use machines. The following adversereactions have been reported in patients treated with Oncaspar along with other chemotherapymedicinal products: somnolence, confusion, dizziness, syncope, seizure.

Patients should be advised not to drive or operate machines while receiving Oncaspar if theyexperience these or other adverse reactions which can impair their ability to drive or operate machines(see section 4.4).

The adverse reactions described in this section are derived from clinical studies data andpost-marketing experience of Oncaspar in ALL patients. The safety profile is based on randomised,controlled, prospective, open label multicentre studies using Oncaspar at a dose of 2500 U/m2administered intravenously as a comparative treatment (studies DFCI 11-001 and AALL07P4). Inaddition, the safety profile included data from other Oncaspar studies such as the study comparing thepharmacokinetics of the liquid and lyophilized formulations of pegaspargase (CL2-95014-002), its rollover study (CL2-95014-003) and studies using the intramuscular route of administration (studies

CCG-1962 and CCG-1991) were also considered to determine the safety profile (see section 5.1 for

CCG-1962 and CCG-1991).

The most common adverse reactions with Oncaspar (observed in at least 2 studies with a frequency of>10%) included: alanine aminotransferase increased, aspartate aminotransferase increased, bloodbilirubin increased, activated partial thromboplastin time prolonged, hypertriglyceridaemia,hyperglycaemia, and febrile neutropenia.

The most common, severe adverse reactions with Oncaspar (graded 3 or 4) observed in studies

DFCI 11-001 and AALL07P4 with a frequency of >5% included: alanine aminotransferase increased,aspartate aminotransferase increased, blood bilirubin increased, febrile neutropenia, hyperglycaemia,lipase increased, and pancreatitis.

Adverse reactions and their frequencies are reported in Table 1. Frequencies are defined by thefollowing convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1: Adverse reactions reported with Oncaspar therapy

MedDRA standard system organclass Adverse reaction

Infections and infestations Common: Infections, sepsis

Very common: Febrile neutropenia

Blood and lymphatic system disorders Common: Anaemia, coagulopathy

Not known: Bone marrow failure

Immune system disorders Very common: Hypersensitivity, urticaria, anaphylactic reaction

Not known: Anaphylactic shock.

Very common: Decreased appetite, hyperglycaemia

Metabolism and nutrition disorders Common: Hyperlipidaemia, hypercholesterolaemia

Not known: Diabetic ketoacidosis, hypoglycaemia

Psychiatric disorders Not known: Confusional state

Common: Seizure, peripheral motor neuropathy, syncope

Nervous system disorders Rare: Posterior reversible leukoencephalopathy syndrome

Not known: Somnolence, tremor*

Very common: Embolism**

Vascular disorders Common: Thrombosis***

Not known: Cerebrovascular accident, haemorrhage, superiorsagittal sinus thrombosis

Respiratory, thoracic and mediastinaldisorders Common: Hypoxia

Very common: Pancreatitis, diarrhoea, abdominal pain, nausea

Gastrointestinal disorders Common: Vomiting, stomatitis, ascites

Rare: Pancreatitis necrotising, pancreatitis haemorrhagic

Not known: Pancreatic pseudocyst, parotitis*

Common: Hepatotoxicity, fatty liver

Hepatobiliary disorders Rare: Hepatic necrosis, jaundice, cholestasis, hepatic failure

Not known: Veno-occlusive disease

Skin and subcutaneous tissue Very common: Rashdisorders Not known: Toxic epidermal necrolysis*

Musculoskeletal and connective tissue Common: Pain in extremitiesdisorders Not known: Osteonecrosis (see sections 4.4 and 4.5)

Renal and urinary disorders Not known: Renal failure acute*

General disorders and administrationsite conditions Not known: Pyrexia

Very common: Weight decreased, hypoalbuminaemia, alanineaminotransferase increased, aspartate aminotransferase

Investigations increased, hypertriglyceridaemia, blood fibrinogen decreased,lipase increased, amylase increased, activated partialthromboplastin time prolonged, blood bilirubin increased,antithrombin III decreased****, neutrophil count decreased****

MedDRA standard system organclass Adverse reaction

Common: Prothrombin time prolonged. international normalisedratio increased, hypokalaemia, blood cholesterol increased,hypofibrinogenaemia, gamma-glutamyl transferase increased

Not known: Blood urea increased, anti-pegaspargase antibodies,platelet count decreased, hyperammonaemia

*Adverse reactions observed with other asparaginases in the class

**Cases of pulmonary embolism, venous thrombosis, venous thrombosis limb, and thrombophlebitis superficialwere observed in DFCI 11-001

***Legend: CNS thrombosis

**** Cases of antithrombin III and neutrophil count decreased were observed in CL2-95014-002 and

CL2-95014-003 studies

The following adverse reactions have been observed in association with asparaginase therapy.

Although they have not been specifically associated with the use or pegaspargase, they may occur withthe use of Oncaspar:

Oncaspar can cause mild to moderate myelosuppression, and all three blood cell lines can be affected.

About half of all serious haemorrhages and thromboses affect cerebral vessels and can lead to e.g.,stroke, seizure, headache or loss of consciousness.

Oncaspar may cause central nervous system dysfunctions manifesting as convulsions, and lessfrequently confusional state and somnolence (mildly impaired consciousness).

In rare cases, a reversible posterior leukoencephalopathy syndrome (RPLS) may occur.

In very rare cases, mild tremor in the fingers has been described.

About half of patients develop mild to moderate gastrointestinal reactions such as loss of appetite,nausea, vomiting, abdominal cramps, diarrhoea and weight loss.

Acute pancreatitis can occur commonly. There have been isolated reports of formation of pseudocysts(up to four months after the last treatment).

Haemorrhagic or necrotising pancreatitis occurs rarely. One case of pancreatitis with simultaneousacute parotitis has been described with L-asparaginase treatment. In single cases, haemorrhagic ornecrotising pancreatitis with fatal outcome has been reported.

Serum amylase can rise during and also after the conclusion of Oncaspar therapy.

Acute renal failure may develop in rare cases during treatment with L-asparaginase-containingregimens.

Allergic reactions can manifest on the skin. One case of toxic epidermal necrolysis (Lyell‘s syndrome)has been described in association with L-asparaginase.

Alterations in endocrine pancreatic function are observed commonly and are expressed mainly in theform of abnormal glucose metabolism. Both diabetic ketoacidosis and hyperosmolar hyperglycaemiahave been described, which generally respond to administration of insulin.

An alteration in serum lipid levels was observed and changes in serum lipid values, in most caseswithout clinical symptoms, are very common.

A rise in serum urea occurs regularly, is dose-independent and nearly always a sign of pre-renalmetabolic imbalance.

Pyrexia can occur after the injection, which usually subsides spontaneously.

Specific antibodies to pegaspargase have been detected; uncommonly they were associated withhypersensitivity reactions. Neutralising antibodies reducing clinical efficacy were also recorded.

Hypersensitivity reactions to Oncaspar, including life-threatening anaphylaxis, angioedema, lipswelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus andrash, can occur during therapy (see sections 4.3 and 4.4).

Alteration of liver parameters is common. A dose-independent rise in serum transaminases, and serumbilirubin is commonly observed.

A rapid weight gain, fluid retention with ascites, hepatomegaly, associated with rapid increase ofserum bilirubin and persistent thrombocytopenia might indicate a risk of developing a severe VOD,which if left untreated, can be fatal (see section 4.4).

Fatty liver can be observed very frequently. There have been rare reports of cholestasis, icterus,hepatic cell necrosis and hepatic failure with fatal outcome.

Impaired protein synthesis can lead to a decline in the serum proteins. There is a dose-independentdecrease in serum albumin in the majority of patients during the treatment.

The types of adverse reactions with Oncaspar are similar to those observed with native non-pegylated

L-asparaginase (e.g., native E. coli asparaginase).

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V

Cases of accidental overdose have been reported with Oncaspar. Following overdose, increased liverenzymes, rash and hyperbilirubinaemia have been observed. There is no specific pharmacologicaltreatment for the overdose. In case of overdose, patients must be carefully monitored for signs andsymptoms of adverse reactions, and appropriately managed with symptomatic and supportivetreatment.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other antineoplasticagents, ATC code: L01XX24

The mechanism of action of L-asparaginase is the enzymatic cleavage of the amino acid L-asparagineinto aspartic acid and ammonia. Depletion of L-asparagine in blood results in inhibition ofprotein-synthesis, DNA-synthesis and RNA-synthesis, especially in leukaemic blasts which are notable to synthesise L-asparagine, thus undergoing apoptosis.

Normal cells, in contrast, are capable of synthesising L-asparagine and are less affected by its rapiddepletion during treatment with the enzyme L-asparaginase. The PEGylation does not change theenzymatic properties of L-asparaginase, but it influences the pharmacokinetics and immunogenicity ofthe enzyme.

Anti-leukaemic effect of L-asparaginase is related to a sustained L-asparagine depletion in blood andcerebrospinal fluid (CSF). The pharmacodynamic (PD) effect of Oncaspar was assessed afterintramuscular (Study CCG-1962) and intravenous administration (AALL07P4).

In Study CCG-1962, PD effect of Oncaspar was assessed through serial measurements of asparaginein serum (n=57) and CSF (n=50) of newly diagnosed paediatric patients with standard-risk ALL whoreceived three intramuscular doses of Oncaspar (2,500 Units/m2 BSA), one each during induction andtwo during delayed intensification treatment phases. A reduction in serum asparagine concentrationwas evident by the 4th day after the first Induction dose and reached an apparent nadir by the 10th dayafter the dose. Serum asparagine concentrations of approximately 1 µM persisted for approximately3 weeks. Asparagine concentration fell to <3 µM when asparaginase activity was >0.1 U/mL. CSFasparagine of 2.3 µM pre-treatment fell to 1.1 µM on Day 7 and 0.6 µM on Day 28 of Induction(see Clinical efficacy and safety).

In Study AALL07P4, the PD effect of Oncaspar was assessed in 47 evaluable subjects with high risk

B-precursor ALL who received intravenous doses of Oncaspar 2,500 U/m2 BSA during the Inductionand Consolidation phases. Plasma L-asparagine concentrations were depleted to below the assay limitof quantification within 24 hours following the Induction and first Consolidation dose of Oncaspar anddepletion was sustained for approximately two weeks. CSF asparagine concentrations were reduced bythe 4th day following the Induction dose, and remained largely undetectable by the 18th day afterdosing.

Based on results from these two studies, a 2,500 U/m2 BSA dose of Oncaspar administeredintramuscular (CCG-1962) and intravenous (AALL07P4) provides maintenance of L-asparaginedepletion for approximately two weeks following dosing.

Oncaspar efficacy and safety were evaluated on the basis of three clinical studies using Oncasparsolution for injection/infusion in the first line treatment of ALL: Study CCG-1962 in standard risk

ALL patients; Study AALL07P4 in high risk ALL patients; Study DFCI 11-001 enrolled both standardand high-risk ALL patients.

Oncaspar efficacy in ALL in patients with relapse/refractory disease and a history of prior clinicalallergic reaction to native E. coli L-asparaginase was based on a pool of 94 patients from sixopen-label studies [ASP-001, ASP-201A, ASP-302, ASP-304, ASP-400 and ASP-001C/003C].

First-Line (ALL patients non-hypersensitive to native E. coli L-asparaginase)

The safety and efficacy of Oncaspar was evaluated in an open-label, multicentre, randomised,active-controlled study (Study CCG-1962). In this study, 118 paediatric patients aged 1 to 9 years withpreviously untreated standard-risk ALL were randomised 1:1 to Oncaspar or native E. coli

L-asparaginase as part of combination therapy. Oncaspar was administered intramuscularly at a doseof 2,500 Units/m2 BSA on Day 3 of the 4-week Induction phase and on Day 3 of each of two 8-week

Delayed Intensification (DI) phases. Native E. coli L-asparaginase was administered intramuscularlyat a dose of 6,000 Units/m2 BSA three times weekly for a total of 9 doses during induction and for atotal of 6 doses during each delayed intensification phase.

The primary determination of efficacy was based on demonstration of similar asparagine depletion(magnitude and duration) in the Oncaspar and native E. coli L-asparaginase arms. Theprotocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤1 µM.

The proportion of patients with this level of depletion was similar between the 2 study arms during all3 phases of treatment at the protocol-specified time points.

In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose ofasparaginase in the treatment phase and remained low for approximately 3 weeks for both Oncasparand native E. coli L-asparaginase arms. Serum asparagine concentrations during the induction phaseare shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensificationphases are similar to the pattern of serum asparagine depletion in the induction phase.

Figure 1: Mean (± standard error) serum asparagine during Study CCG-1962 induction phase100.0

Native E .E c. coolil iL -

Oncaspar®

Asparaginase10.01.00.10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Days After First Dose of L-Asparaginase

Note: Oncaspar (2,500 Units/m2 BSA intramuscular) was administered on Day 3 of the 4-weekinduction phase. Native E. coli L-asparaginase (6,000 Units/m2 BSA intramuscular) wasadministered 3 times weekly for 9 doses during induction.

CSF asparagine concentrations were determined in 50 patients during the induction phase. CSFasparagine decreased from a mean pre-treatment concentration of 3.1 µM to 1.7 µM on Day 4 ± 1 and1.5 µM at 25 ± 1 days after administration of Oncaspar. These findings were similar to those observedin the native E. coli L-asparaginase treatment arm.

Event-free survival (EFS) for the Oncaspar and native E. coli L-asparaginase arms is summarised in

Table 2, Study CCG-1962 was not designed to evaluate differences in EFS rates.

Table 2: Event-free survival rate at 3, 5 and 7 years (Study CCG-1962)

Oncaspar native E. coli L-asparaginase3-Year EFS Rate, % 83 79(95% CI) (73, 93) (68, 90)5-Year EFS Rate, % 78 73(95% CI) (67, 88) (61, 85)7-Year EFS Rate, % 75 66(95% CI) (63, 87) (52, 80)

In Study CCG-1962, the most common adverse reactions were infections, including twolife-threatening infections (1 patient in each arm). In general, incidence and type of adverse reactions

Grade 3 and 4 were similar between the two treatment groups. Two patients in the Oncaspar arm had

Asparagine (µM)allergic reactions during Delayed Intensification (DI) DI #1 (Grade 1 allergic reaction and Grade 3hives).

A pilot study was conducted for newly diagnosed patients from 1 to <31 years of age with high risk

B-precursor ALL (Study AALL07P4). This was an open label, controlled, randomised studycomparing an investigational pegylated asparaginase product to Oncaspar as a component ofmulti-agent chemotherapy in the first line treatment of ALL. White blood cell (WBC) criteria were:a) Age 1-10 years: WBC ≥50,000/μL; b) Age 10-30 years: Any WBC; c) Prior steroid therapy: Any

WBC. Patients were not allowed prior cytotoxic chemotherapy with the exception of steroids andintrathecal cytarabine. A total of 166 patients were enrolled in this study; 54 patients were randomisedto treatment with 2,500 U/m2 BSA Oncaspar and 111 patients were randomised to the investigationalpegylated asparaginase product. Oncaspar was administered intravenously at the dose of2,500 Units/m2 BSA during Induction, Consolidation, Delayed Intensification, and Interim

Maintenance phases in patients with high-risk ALL receiving augmented Berlin-Frankfurt-Münstertherapy. The percentage of patients in the Oncaspar treatment arm with evaluable minimal residualdisease (MRD) negative status (<0.1% leukaemia cells in bone marrow) at Day 29 of Induction was80% (40/50). At 4-years, the EFS and overall survival (OS) for the Oncaspar treatment arm were81.8% [95% CI 62.9-91.7%] and 90.4% [95% CI 78.5-95.9%], respectively. Overall, in the groupreceiving Oncaspar, the rate of all grade hypersensitivity was 5.8%, anaphylactic reactions was 19.2%,and pancreatitis 7.7%. Grade 3 or higher febrile neutropenia was 15.4%.

Study DFCI 11-001, conducted by the Dana-Farber Cancer Institute (DFCI), is an ongoing,active-controlled, randomised multicentre study of an intravenous investigational pegylatedasparaginase product versus Oncaspar, in children and adolescents aged 1 to <22 years with newlydiagnosed ALL treated with a DFCI ALL consortium therapeutic backbone. A total of 239 patientswere randomised, 237 of whom were treated with study drug (146 male and 91 female), of these,119 patients (115 with a diagnosis of ALL) were treated with Oncaspar 2500 U/m2. Treatment wasadministered during Induction (Day 7), and then every 2 weeks for a total of 30 weeks post-Inductiontherapy. Randomisation of patients was stratified based on risk group (standard/high/very high risk),including both B- and T-cell ALL. The percentage of patients in the Oncaspar arm with evaluable Low

End-Induction MRD (<0.001 detectable disease) at Day 32 was 87.9% (80/91). The One-year EFSwas 98.0 [95%CI 92.3, 99.5]; the One-year OS was 100 [95% CI 100, 100] in this study.

ALL patients hypersensitive to native E. coli L-asparaginase

Six open-label studies evaluated Oncaspar in relapse/refractory haematological diseases. In thesestudies a total of 94 patients with ALL diagnosis with a history of prior clinical allergic reaction tonative E. coli L-asparaginase were exposed to Oncaspar. One patient received Oncaspar doses of250 and 500 Units/m2 BSA intravenously. The remaining patients were treated with 2,000 or2,500 U/m2 BSA administered intramuscularly or intravenously. Patients received Oncaspar as asingle agent or in combination with multi-agent chemotherapy. Overall, from five studies analysedbased on 65 ALL patients exposed to Oncaspar using the highest therapeutic response during theentire study, complete remission was observed in 30 patients (46%), partial remission in 7 patients(11%) and haematological improvement in 1 patient (2%). In the other study, with 29 hypersensitive

ALL patients exposed to Oncaspar, 11 patients were evaluated for response during induction. Of these,3 patients (27%) achieved complete remission, 1 patient (9%) had partial remission, 1 patient (9%)had haematologic improvement and 2 patients (18%) had therapeutic efficacy. Therapeutic efficacywas defined as a clinical improvement which did not meet the criteria for other beneficial outcomes.

During the maintenance phase, 19 patients were evaluated, with 17 patients (89%) achieving completeremission, and 1 patient (5%) with therapeutic efficacy.

Oncaspar pharmacokinetic properties were based on asparaginase activity measured by an enzymaticassay after intramuscular (CCG-1962) and intravenous (AALL07P4, DFCI 11-001) administration.

In Study CCG-1962, mean asparaginase activity reached peak value of 1 U/mL on Day 5 after theinjection. The mean half-life after absorption from the injection site was 1.7 days and the eliminationhalf-life was 5.5 days. The volume of distribution at steady-state and clearance were estimated at1.86 L/m2 and 0.169 L/m2 per day, respectively.

In Study AALL07P4, PK parameters after a single 2,500 U/m2 intravenous dose during Induction werecalculated by noncompartmental PK analysis from sequential plasma samples and are depicted in

Table 3 (see section 5.1). The Cmax and AUC of Oncaspar trended lower in males, subjects with larger

BMI, and subjects >10 years. During Induction, following a single intravenous dose of Oncaspar2,500 U/m2, asparaginase activity ≥0.1 U/mL was sustained for up to 18 days post-dose in 95.3% ofsubjects.

Table 3: Pharmacokinetic Parameters After a Single intravenous Dose of Oncaspar2,500 U/m2 BSA During Induction (N=47; Study AALL07P4)

PK Parameters Arithmetic Mean (SD)

Cmax (mU/mL)* 1638 (459.1)

Tmax (hr)* 1.25 (1.08, 5.33)†

AUC0-t (mUday/mL)* 14810 (3555)

AUC0-∞ (mUday/mL)ǂ 16570 (4810)t ǂ1/2 (day) 5.33 (2.33)

CL (L/day)ǂ 0.2152 (0.1214)

Vss (L)ǂ 1.95 (1.13)

* N=47 evaluable subjects.† Median (10th, 90th percentiles).ǂ N= 46 evaluable subjects.

In Study DFCI 11-001, assessments of asparaginase activity were performed following a singleintravenous dose of Oncaspar 2,500 U/m2 BSA during Induction, and every two weeks duringpost-Induction (see section 5.1). During Induction, plasma asparaginase activity ≥0.1 U/mL wassustained in 93.5% of subjects 18 days after administration. During the post-Induction phase, a nadir(trough) asparaginase activity above 0.4 U/mL was sustained in 100% of subjects from Week 7 upuntil Week 25. These results indicate that, when Oncaspar 2,500 U/m2 BSA is administered as singleand repeated doses every two weeks, clinically relevant asparaginase activity is sustained over theentire dosing interval (i.e., two weeks).

Patients with newly diagnosed ALL received a single intramuscular injection of Oncaspar (2,500 U/m²

BSA) or native asparaginase from E. coli (25,000 U/m² BSA) or from Erwinia (25,000 U/m² BSA).

The plasma elimination half-life of Oncaspar was statistically significantly longer (5.7 days) than theplasma elimination half-lives of the native asparaginases from E. coli (1.3 days) and Erwinia(0.65 days). The immediate cell death of leukaemic cells in vivo, measured by rhodaminefluorescence, was the same for all three L-asparaginase preparations.

ALL patients with several relapses were treated either with Oncaspar or with native asparaginase from

E. coli as part of an induction therapy. Oncaspar was given intramuscular in a dose of 2,500 U/m²

BSA on days 1 and 15 of induction. The mean plasma half-life of Oncaspar was 8 days innon-hypersensitive patients (AUC 10.35 U/ml/day), and 2.7 days in hypersensitive patients (AUC3.52 U/ml/day).

The controlled studies were not designed to formally evaluate the pharmacokinetics of Oncaspar inspecific populations. A population pharmacokinetic evaluation of Oncaspar based on data obtainedfrom Studies AALL07P4 (IV), DFCI 11-001 (IV), and CCG-1962 (IM) identified that clearance(linear and saturable) increased approximately proportionally to BSA and volume of distributionincreased slightly more proportionally to BSA. No statistically significant differences in PKcharacteristics between male and female subjects were identified in this analysis.

The impact of renal and hepatic impairment on the PK of Oncaspar has not been evaluated. Aspegaspargase is a protein with a high molecular weight, it is not excreted renally, and no change ofpharmacokinetic of Oncaspar in patients with renal impairment is foreseen.

Since the proteolytic enzymes responsible for Oncaspar metabolism are ubiquitously distributed intissues the exact role of the liver is unknown: however any decrease in liver function is not expected topresent clinical relevant problems in the use of Oncaspar.

There are no data available for elderly patients.

Pharmacokinetic/pharmacodynamic nonclinical comparability between the two pharmaceutical formsof Oncaspar, solution for injection/infusion, and powder for solution, was demonstrated in dogs aftersingle and repeated doses (500 U/kg), by the intravenous route. The below mentioned studies wereperformed on the solution for injection/infusion formulation.

Acute toxicity

Only very high doses of pegaspargase given to mice intraperitoneally as a single dose (25,000 -100,000 U/kg body weight) caused the death of 14% of all treated mice. Mild hepatotoxicity wasobserved with the same doses. Adverse reactions were loss of body weight, piloerection and reducedactivity. Reduced splenic weight might be a sign of potential immunosuppressant effect of thetreatment.

Pegaspargase was well tolerated both in rats and dogs when administered intravenously in single dosesup to 500 U/kg body weight.

A 4-week study in rats treated with a dose of pegaspargase of 400 U/kg/day intraperitoneal resulted ina fall in food intake and body weight compared to the control group.

A 3-month study in mice with pegaspargase at doses up to 500 U/kg intraperitoneally orintramuscularly resulted in slight hepatocellular changes only at the highest intraperitoneal dose.

A temporary suppression in body weight gain and a temporary reduction in total leukocyte countswere observed in dogs which were treated with pegaspargase 1200 U/kg weekly for 2 weeks.

Increased serum glutamic pyruvic transaminase activity also occurred in one out of four dogs.

No immunogenic response was detected in a 12-week study in mice in which pegaspargase wasadministered weekly at the dose of 10.5 U/mouse intramuscularly or intraperitoneally.

No studies of reproductive toxicity were conducted with pegaspargase.

Embryotoxicity studies with L-asparaginase have showed evidence of teratogenic potential in ratstreated from day 6 to 15 of gestation with a No Observed Effect Level (NOEL) for teratogenic effectsat 300 U/kg intravenously. In rabbits, doses of 50 or 100 U/kg intravenous on days 8 and 9 ofgestation induced viable fetuses with congenital malformations: no NOEL has been determined.

Multiple malformations and embryolethal effects were observed with doses in the therapeutic range.

Investigations of the effect on fertility and peri- and postnatal development were not conducted.

Carcinogenicity, mutagenicity, fertility

Long-term investigations of carcinogenicity or studies of the effect on fertility in animals were notconducted with pegaspargase.

Pegaspargase was not mutagenic in the Ames test using Salmonella typhimurium strains.

Disodium phosphate heptahydrate

Sodium dihydrogen phosphate monohydrate

Sodium chloride

Sucrose

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial:3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours below 25°C. From amicrobiological point of view, unless the method of reconstitution precludes the risk of microbialcontamination, the product should be used immediately. If not used immediately, in-use storage timesand conditions are the responsibility of the user.

Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-8°C. From amicrobiological point of view, the product should be used immediately. If not used immediately,in-use storage times and conditions prior to use are the responsibility of the user and would normallynot be longer than 24 hours at 2°C-8°C, unless reconstitution/dilution has taken place in controlled andvalidated aseptic conditions.

Store in a refrigerator (2°C-8°C).

Do not freeze.

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

Type I flint glass vial with chlorobutyl elastomer stopper, capped with a 20 mm aluminium flip-offseal, containing 3,750 U pegaspargase.

Pack size of 1.

This medicinal product can cause irritation on contact. The powder must therefore be handled andadministered with particular caution. Inhalation of the vapour and contact with the skin and mucousmembranes, especially the eyes, must be avoided; if the medicinal product comes in contact with eyes,skin or mucous membranes, rinse immediately with plenty of water for at least 15 minutes.

Oncaspar is to be administered intravenously or intramuscularly after reconstitution of the product.

The powder must be reconstituted with 5.2 ml water for injections prior to administration (seesection 4.2).

Instructions for handling1. Staff should be trained in how to handle and transfer the medicinal product (pregnant staffshould be excluded from working with this medicinal product).2. Aseptic technique must be used.3. Procedures for proper handling of antineoplastic agents should be observed.4. The use of disposable gloves and protective garments is recommended when handling

Oncaspar.5. All items for administration or cleaning, including gloves, should be placed in high-risk wastedisposal bags for high-temperature incineration.

Reconstitution1. 5.2 ml water for injections are injected into the vial using a syringe and 21 gauge needle.2. The vial should be gently swirled until the powder is reconstituted.3. After reconstitution, the solution should be clear, colourless and free from visible foreignparticles. Do not use if the reconstituted solution is cloudy or if a precipitate has formed. Do notshake.

4. The solution should be used within 24 hours after reconstitution, when stored below 25°C.

Administration1. Parenteral medicinal products should be inspected for particulate matter prior to administration,only a clear, colourless solution free from visible foreign particles should be used.2. The medicinal product should be administered intravenously or intramuscularly. The solutionshould be administered slowly.

For intramuscular injection, the volume should not exceed 2 ml in children and adolescents and3 ml in adults.

For intravenous administration, the reconstituted solution should be diluted in 100 ml sodiumchloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution.

The diluted solution can be given over 1 to 2 hours together with an already-running infusion ofeither sodium chloride 9 mg/ml or 5% glucose. Do not infuse other medicinal products throughthe same intravenous line during administration of Oncaspar (see section 4.2).

After dilution, the solution should be used immediately. If immediate use is not possible, thediluted solution can be stored at 2°C-8°C for up to 48 hours (see section 6.3).

Oncaspar is for single use only. Any unused medicinal product or waste material should be disposedof in accordance with local requirements.

Les Laboratoires Servier50, rue Carnot92284 Suresnes cedex

France

EU/1/15/1070/002

Date of first authorisation: 14 January 2016

Date of latest renewal: 20 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.